title: Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism signature.
abstract: BACKGROUND
  Bone metastases represent a common and severe complication in breast cancer, and the involvement of cancer stem cells (CSCs) in the promotion of bone metastasis is currently under discussion. Here, we used a human-in-mice model to study bone metastasis formation due to primary breast CSCs-like colonisation.
  
  
  METHODS
  Primary CD44⁺CD24⁻ breast CSCs-like were transduced by a luciferase-lentiviral vector and injected through subcutaneous and intracardiac (IC) routes in non-obese/severe-combined immunodeficient (NOD/SCID) mice carrying subcutaneous human bone implants. The CSCs-like localisation was monitored by in vivo luciferase imaging. Bone metastatic CSCs-like were analysed through immunohistochemistry and flow cytometry, and gene expression analyses were performed by microarray techniques.
  
  
  RESULTS
  Breast CSCs-like colonised the human-implanted bone, resulting in bone remodelling. Bone metastatic lesions were histologically apparent by tumour cell expression of epithelial markers and vimentin. The bone-isolated CSCs-like were CD44⁻CD24⁺ and showed tumorigenic abilities after injection in secondary mice. CD44⁻CD24⁺ CSCs-like displayed a distinct bone tropism signature that was enriched in genes that discriminate bone metastases of breast cancer from metastases at other organs.
  
  
  CONCLUSIONS
  Breast CSCs-like promote bone metastasis and display a CSCs-like bone tropism signature. This signature has clinical prognostic relevance, because it efficiently discriminates osteotropic breast cancers from tumour metastases at other sites.
authors.affiliation: CeRMS (Center for Experimental Research and Medical Studies), A.O. Città della Salute e della Scienza di Torino, via Santena 5, 10126 Torino, Italy.
authors.forename: L
authors.initials: L
authors.lastname: D'Amico
authors.forename: S
authors.initials: S
authors.lastname: Patanè
authors.forename: C
authors.initials: C
authors.lastname: Grange
authors.forename: B
authors.initials: B
authors.lastname: Bussolati
authors.forename: C
authors.initials: C
authors.lastname: Isella
authors.forename: L
authors.initials: L
authors.lastname: Fontani
authors.forename: L
authors.initials: L
authors.lastname: Godio
authors.forename: M
authors.initials: M
authors.lastname: Cilli
authors.forename: P
authors.initials: P
authors.lastname: D'Amelio
authors.forename: G
authors.initials: G
authors.lastname: Isaia
authors.forename: E
authors.initials: E
authors.lastname: Medico
authors.forename: R
authors.initials: R
authors.lastname: Ferracini
authors.forename: I
authors.initials: I
authors.lastname: Roato
mesh_terms: D000328:Adult; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005812:Genes, Switch / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D059467:Transcriptome / Q000502:physiology